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Query: UMLS:C0596978 (Leukemia)
 15,069 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment-related acute myeloid leukemia (t-AML) following successful therapy of a primary malignancy has been recognized with increasing frequency among cancer survivors over the past several years. Many of these t-AML cases are associated with the use of intensive chemotherapy regimens that employ one or more agents which target eukaryotic topoisomerase II (topo II), and demonstrate non-random chromosomal translocations involving either the MLL (ALL-1, HRX) gene at 11q23 or the AML1 gene at 21q22. Although many investigators have speculated that these translocations are induced by the therapeutic use of topo II inhibitors, the molecular sequence of events by which topo II inhibitors might induce a chromosomal translocation are not well understood. We describe here the reproducible induction of highly specific, double-strand DNA cleavage at a specific site within the AML1 locus by topo II inhibitors. This DNA cleavage, which maps to a region of the AML1 locus frequently disrupted by chromosomal translocations, can be induced in several cell lines, with multiple different topo II inhibitors, indicating that this phenomenon is not restricted to a specific cell type or specific topo II inhibitor. It is conceivable that site-specific double-strand DNA cleavage within the AML1 locus induced by topo II inhibitors represents the initial molecular event leading to a chromosomal translocation and t-AML.
Leukemia 1997 Apr
PMID:Topoisomerase II inhibitors induce DNA double-strand breaks at a specific site within the AML1 locus. 909 88

One of the most serious consequences of cancer therapy is the development of a second cancer, especially leukemia. Several distinct subsets of therapy-related leukemia can now be distinguished. Classic therapy-related myeloid leukemia typically occurs 5 to 7 years after exposure to alkylating agents and/or irradiation, has a myelodysplastic phase with trilineage involvement, and is characterized by abnormalities of the long arms of chromosomes 5 and/or 7. Response to treatment is poor, and allogenic bone marrow transplantation is recommended. Leukemia following treatment with agents that inhibit topoisomerase II, however, has a shorter latency, no preleukemic phase, a monoblastic, myelomonocytic, or myeloblastic phenotype, and balanced translocations, most commonly involving chromosome bands 11q23 or 21q22. The MLL gene at 11q23 or the AML1 gene at 21q22 are almost uniformly rearranged. MLL is involved with many fusion gene partners. Therapy-related acute lymphoblastic leukemia also occurs with 11q23 rearrangements. Therapy-related leukemias with 11q23 or 21q22 rearrangements, inv(16) or t(15;17), have a more favorable response to treatment and a clinical course similar to their de novo counterparts.
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PMID:Myeloid leukemia after hematotoxins. 911 10

To determine the frequency and prognostic significance of recently described genetic lesions in pediatric acute lymphoblastic leukemia (ALL), all cases with available leukemic cell samples treated on St Jude Study XII were analyzed by molecular techniques for alterations of the p16, MLL and ETV6 genes. Homozygous p16 deletion was seen in 36 of 155 cases, including 14 of 23 T cell cases, but had no prognostic value. Rearrangement of MLL was seen in nine of 170 cases (5%) and conferred a poor prognosis, with a 5-year EFS estimate of only 11 +/- 7%, compared with 74 +/- 5% for the germline MLL group (P=0.0001). By contrast, rearrangement of ETV6 was found in 35 cases (21%) and was significantly associated with a better outcome (5-year EFS estimates: 87 +/- 7% vs 64 +/- 6%). In a Cox regression model adjusted for age, DNA index, race, leukocyte count, treatment group, and CNS status, ETV6 rearrangement retained independent prognostic significance (two-sided P value 0.012). Thus, in this uniformly treated group of patients, we confirmed the unfavorable prognostic significance of MLL rearrangement and demonstrated the favorable impact of ETV6 rearrangement, suggesting that these factors be added to ALL risk classification schemes.
Leukemia 1997 Aug
PMID:Genetic studies of childhood acute lymphoblastic leukemia with emphasis on p16, MLL, and ETV6 gene abnormalities: results of St Jude Total Therapy Study XII. 926 70

A 20-year-old Japanese man was referred because of severe pancytopenia with 14% of abnormal blasts in hypocellular bone marrow. After treatment by granulocyte colony-stimulating factor (G-CSF) and transfusions of red blood cells, spontaneous remission was subsequently achieved. After 3 months' remission, however, the patient developed AML characterized by the abnormal karyotype: 46XY,+8,t(9;11)(p22;q23). FISH study revealed the presence of trisomy 8 clone also in the hypoplastic state. While MLL-AF9 chimeric mRNA was observed in leukemic cells, it was not detectable in bone marrow cells from the hypoplastic state by RT-PCR. This is the first report of a trisomy 8 clone which evolved into one with a MLL gene rearrangement.
Leukemia 1997 Aug
PMID:Clonal evolution to acute myeloblastic leukemia with MLL gene rearrangement from trisomy 8 clone. 926 97

We describe two new human leukemia cell lines, MOLM-13 and MOLM-14, established from the peripheral blood of a patient at relapse of acute monocytic leukemia, FAB M5a, which had evolved from myelodysplastic syndrome (MDS). Both cell lines express monocyte-specific esterase (MSE) and MLL-AF9 fusion mRNA. Gene fusion is associated with a minute chromosomal insertion, ins(11;9)(q23;p22p23). MOLM-13 and MOLM-14 are the first cell lines with, and represent the third reported case of, MLL gene rearrangement arising via chromosomal insertion. Both cell lines carry trisomy 8 which was also present during the MDS phase, as well as the most frequent trisomies associated with t(9;11), ie, +6, +13, +19 variously present in different subclones. Despite having these features in common, differences in antigen expression were noted between the two cell lines: that of MOLM-13 being CD34+, CD13-, CD14-, CD15+, CD33+; whereas MOLM-14 was CD4+, CD13+, CD14+, CD15+, CD33+. Differentiation to macrophage-like morphology could be induced in both cell lines after stimulation with INF-gamma alone, or in combination with TNF-alpha, which treatment also induced or upregulated, expression of certain myelomonocyte-associated antigens, including CD13, CD14, CD15, CD64, CD65 and CD87. Together, these data confirm that both cell lines are likely to be novel in vitro models for studying monocytic differentiation and leukemogenesis.
Leukemia 1997 Sep
PMID:Two acute monocytic leukemia (AML-M5a) cell lines (MOLM-13 and MOLM-14) with interclonal phenotypic heterogeneity showing MLL-AF9 fusion resulting from an occult chromosome insertion, ins(11;9)(q23;p22p23). 930

A novel variant of the chimerical MLL-AF10 mRNA transcript was detected in a pediatric patient with acute myeloid leukemia (AML) by a new asymmetric reverse-transcription polymerase chain reaction (ART-PCR) method. Sequence analysis of the fusion region on the amplified cDNA fragment showed an in-frame joining of exon e5 of the MLL gene and position 1931 of the cDNA sequence of the AF10 gene, giving rise to a new MLL-AF10 transcript. The presence of the new chimerical mRNA product in a sample from the patient was confirmed by classical RT-PCR.
Leukemia 1997 Sep
PMID:A novel MLL-AF10 fusion mRNA variant in a patient with acute myeloid leukemia detected by a new asymmetric reverse transcription PCR method. 930 18

Although the presence of a chromosome 11q23 breakpoint is of recognized poor prognosis in acute lymphoblastic leukemia, its prognostic significance in acute myeloid leukemia (AML) has been the object of conflicting reports, perhaps reflecting the possibility of different entities. It has been found that only typical and generally balanced 11q23 chromosomal anomalies involve the MLL gene while atypical and generally unbalanced do not. To determine whether these two categories of AML patients had different initial characteristics and evolution, supporting different pathogenetic mechanisms, we analyzed clinical and biologic characteristics of newly diagnosed AML patients with balanced 11q23 breakpoint and/or MLL rearrangement seen over a 10-year period in our institution and compared them to cases with unbalanced 11q23 anomaly seen over the same period. These two categories of patients were compared with newly diagnosed patients with normal karyotype and no MLL rearrangement when tested, seen over the same period of time and treated similarly. Over this period, 442 newly diagnosed adult (> 15 years) AML seen in our institution had a successful karyotype performed before any therapy. Thirty-six cases (8%) had a chromosome 11q23 breakpoint including 19 cases with a balanced translocation or inversion and 17 cases with an unbalanced anomaly. Eighty-seven recently diagnosed cases of AML, for whom frozen cellular material was available, were analyzed by Southern blot for the presence of MLL gene rearrangement. Fourteen cases (16% of the tested cases) had a rearrangement of the MLL gene, including seven cases with an apparently successful karyotype not showing any 11q23 breakpoint and two cases with no available karyotype. The only case with unbalanced 11q23 chromosomal anomaly which was tested had no MLL rearrangement. There was a clear-cut clinical difference between the 28 patients having a balanced 11q23 anomaly/MLL rearrangement and the 17 patients having an unbalanced chromosomal anomaly: AML with unbalanced 11q23 anomalies occurred in older patients (P = 0.07) tended to be less frequently associated with previous exposure to topoisomerase II-active drugs and with M4/M5 FAB cytological subtypes, were always associated with other chromosomal anomalies (P < 0.0001), expressed more frequently the CD34 antigen (P = 0.05) and were of considerably poorer prognosis for achievement of CR (P = 0.005) and survival (P = 0.0005). When compared to the control population, patients with balanced anomalies had more frequent history of toxic exposure (P = 0.0003) particularly to topoisomerase II-active drugs, tended to be more frequently of M4/M5 FAB subtypes (P = 0.07), expressed more frequently HLA-DR antigen (P = 0.02) and had shorter DFS (P = 0.02). Patients with unbalanced anomalies had more frequent splenomegaly (P = 0.009), lower WBC count (P = 0.04), and much poorer prognosis for CR achievement (P = 0.0001), survival (P < 0.0001) and DFS (P = 0.01). This study confirms the high frequency of 11q23 chromosomal breakpoint/MLL rearrangement in adult AML and the probable existence of two different entities with different clinical features according to the presence of a balanced or unbalanced cytogenetic abnormality, the latter being not associated with MLL rearrangement.
Leukemia 1998 Jan
PMID:Clinical and biological characteristics of adult de novo and secondary acute myeloid leukemia with balanced 11q23 chromosomal anomaly or MLL gene rearrangement compared to cases with unbalanced 11q23 anomaly: confirmation of the existence of different entities with 11q23 breakpoint. 943 17

p16 and p15 genes are putative tumor suppressor genes located on chromosome 9p21. In acute leukemias, alterations of p16 and p15 genes have been reported to occur exclusively in lymphoid lineage. We analyzed alterations of p16 and p15 genes in 46 acute leukemias with MLL gene rearrangements by Southern blot analysis, and investigated the association with clinical characteristics. We identified homozygous deletion of p16 and p15 genes in five (19%) of 27 acute lymphoblastic leukemias (ALLs) and in two (11%) of 19 acute myeloid leukemias (AMLs). Patients with homozygous deletion of p16 and p15 genes showed higher average leukocyte counts (343 x 10(9)/l vs 271 x 10(9)/l) and lower estimated 2-year survival rates than those with normal p16 and p15 genes (14.3 vs 30.7%), although the differences were not statistically significant. In addition, we investigated mutation of p16 gene by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) in 31 patients, but no mutation was found in the patients tested. Our results suggest that alterations of p16 and p15 genes are involved in a subset of acute leukemias with MLL gene rearrangement not only of lymphoid but also of myeloid phenotype. Homozygous deletion of p16 and p15 genes may be a possible adverse prognostic factor, although further analysis would be needed to confirm it.
Leukemia 1997 Dec
PMID:Alterations of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features. 944 29

11q23 translocations (t(11q23)) are recurring cytogenetic abnormalities in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia, involving the same gene, ALL1 (or MLL). Mixed lineage antigen expression has been reported in these leukemias, but its frequency and clinical significance are unknown. We immunophenotyped leukemia cells from 19 adult de novo AML patients with t(11q23) by multiparameter flow cytometry. Translocations included t(6;11)(q27;q23), t(9;11)(p22;q23), t(9;11;19)(p22;q23;q13.3), t(2;11)(11;17)(q37;q11q23;q11), t(11;17)(q23;q25), t(11;19)(q23;p13.1), t(11;19)(q23;p13.3) and t(11;22)(q23;q11). FAB types were M4 and M5. The committed stem cell and myeloid antigens HLADr, CD4dim, CD11b, CD13, CD15, CD32, CD33, CD38 and CD64 were each expressed in 80-100% of cases, and the early stem cell and lymphoid antigens CD34, CD56, CD3, CD2 and CD7 in 42, 39, 16, 5 and 5%, respectively. Antigen expression frequencies did not differ from those in 443 adequately karyotyped M4 and M5 cases without t(11q23). Fifteen patients (79%) attained complete remission (CR); median CR duration and survival were 10.0 and 15.1 months. CR duration and survival did not correlate with antigen expression. In particular, patients with t(9;11) survived longer than those with other t(11q23) (median not reached vs 7.6 months; P = 0.048), but antigen expression did not differ in the two groups. Thus frequencies of lymphoid antigen expression are similar in AML with t(11q23) and in other FAB M4 and M5 cases, treatment outcome does not differ in t(11q23) cases with and without lymphoid antigen expression, and better outcome of patients with t(9;11) compared to other t(11q23) does not correlate with differences in antigen expression. Mixed lineage antigen expression is not a distinctive feature of AML with t(11q23).
Leukemia 1998 Mar
PMID:Acute myeloid leukemia with 11q23 translocations: myelomonocytic immunophenotype by multiparameter flow cytometry. 952 25

A patient previously diagnosed with chronic neutrophilic leukemia (CNL) was studied using fluorescent in situ hybridization (FISH) to determine clonality of neutrophils. By cytogenetic studies the patient's blood and bone marrow had an 11q14 deletion and were negative for the Philadelphia (Ph) chromosome. FISH was performed on peripheral blood smears using probes for the bcr/abl translocation and a probe for 11q23 (MLL). The patient's white blood cells were negative for the bcr/abl translocation; neutrophils and eosinophils, but not lymphocytes, were monosomic for the 11q23 probe indicating a clonal population within the neutrophil population.
Leukemia 1998 Apr
PMID:Demonstration of clonality in neutrophils using FISH in a case of chronic neutrophilic leukemia. 955 23


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